DE1518311B1 - N- (2-Diaethylaminoaethyl) -2-methoxy-3,4- or 4,5-methylenedioxybenzamide and their pharmacologically non-toxic acid addition salts - Google Patents

Description

2. Effect on the central nervous system

The antagonism to tremorin in the mouse was determined as follows: the analgesic effect of tremorin when administered intramuscularly was determined as a function of dose, from which the analgesic dose 100 could be calculated.

the effect of N- (2-diethylaminoethyl) - 20 The antagonistic product was intra-

2 - methoxy - 3,4 - methylenedioxybenzamide hydrochloride (I) and N- (2-diethylaminoethyl) -2-methoxy-4,5-methyldioxybenzamide hydrochloride (II) tested against two known compounds. The here peritoneal groups to 10 mice with increasing Dose, and tremorin (7.5 mg / kg) was administered at the 100 analgesic dose at the same time. 60 minutes later the sensitivity became the

The results obtained are summarized below: 25 animals tested by the Haffner method, the following

holds, these are converted to the free bases.

1. Antiemetic properties measured: it becomes a painful one Stimulus is generated by attaching moor tweezers to the base of the tail of a mouse. Normally the animal tries to break free from it. The anal

The antagonistic effect compared to the apogenic effect is considered to have occurred in every mouse,

Morphine was named after one of Chen and E η s ο r in "Journal of Pharmacology and Experimental Therapeutics", 1950, 98, pp. 246 to 250, and by Ducrοt and Decourt in “Comptes rendues des who does not try to remove the tweezers within 20 seconds. From the percentage of not animals made analgesic as a function of the logarithm of the dose, a curve is obtained from

seances de la Societe de Biologie et de ses filiales «, 35 which graphically shows the effective antitremorin dose 50

1951, 145, pp. 356 and 357, the method described on the dog was determined. Thereafter, the substances to be tested are administered subcutaneously or orally in each case 30 or 60 minutes before the administration of apomorphine (100 μg / kg / sc), and the animal is _{observed for V 2} hours after the injection of the alkaloid. In the experiments described here, a group of four dogs was used, and cross-tests were also carried out: two animals were used for comparison, the other two received the relevant dose of the substance to be examined. One week later, the reverse order was followed and the number of vomiting per group before and after the administration was determined. If one is wearing (DE ₅₀ ) it can be determined. The results compiled in Table 2 were obtained.

Table 2
Antitremorin activity

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I (example 1)

II (example 2)

the protection obtained in percent logarithmically against 50 ^N f -dimethylaminopropyl) -the dose administered, a curve is obtained from 3-chlorophenothiazm (known

which can determine the effective dose DE _{50 of} the compounds examined. The values given in Table I below were found:

Table 2 shows that to achieve a

DE ₅₀ (mg / kg)

37.4 1.9

40 mg / kg effect of 10%

Table 1

Antiemetic activity

(with 100, itg / kg apomorphine, in dogs)

55

link

I (example I)

II (example 2)

N- (3'-dimethylaminopropyl) -3-chloro-

pheno-thiazine (known)

N-diethylaminoethyl-2-methoxy-4-amino-5-chlorobenzamide (known)

DE ₅₀ fcg / kg / sc)

18.5
240

500
26.8 50% action required dose of N- (3-dimethylaminopropyl) -3 - chlorophenothiazine is much higher than the DE ₅₀ values of the compounds of Examples 1 and 2, since 40 mg of the known compound is only analgesic Effect of 10% achieved.

In the following Table 3 are the values of the antimescaline activities given, according to the method of Chen and B ο h η e r, described in »Archives Internationales de Pharmacodynamie ", 1960, Vol. 125, No. 1 and 2, p. 2, as well as by D e e g a η and Cook, "Journal of Pharmacology and Experimental Therapeutics", 1958, Vol. 122, p. 17a.

Table 3

Antimescaline activity

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I (example 1)

II (example 2)

N- (3'-Dimethylaminopropyl) -3-chlorophenothiazine (known)

N-diethylaminoethyl-2-methoxy-4-amino-5-chlorobenzamide (known)

DE ₅₀ (mg / kg / ip)

23.8 7.6

1.8

7.3

From Table 3 it can be seen that the benzamides I and II are better tolerated. in the In contrast to N- (3'-dimethylaminopropyl) -3-chlorophenothiazine, they do not have a dampening effect on the central nervous system. This is excited by mescaline, a small dose of N - (3 '- dimethylaminopropyl) 3-chlorophenothiazine neutralizes this activity. Thus, compounds I and II allow a more adaptable one Treatment.

Also in their cataleptic activity, the compounds of Examples 1 and 2 are the N- (3'-dimethylaminopropyl) - 3 - superior to chlorphenothiazine. The cataleptic effect was observed in the the method described in the following literature:

Tedeschi, Archives Internationales de Pharmakodynamie, 1959, Vol. 122, pp. 129 to 143;

Taeschler and Ferletti, The Journal of Physiology (New York), 1959, Vol. 51, pp. 873-878; B ο i s s i e r, Therapy, 1960, pp. 73 to 77;

Boissier and Simon, Therapy, 1963, Vol. 18, pp. 1257 to 1277.

Table 4
Cataleptic activity

link dose effect I (example 1)
II (example 2),
N- (3'-dimethylamino-
propyl) -3-chloropheno-
thiazine (known) 50 mg / kg / sc
50 mg / kg / sc
DE ₅₀
= 7 mg / kg / sc 20%
20%

Table 5

link i.v. DL ₅₀ (mouse)
Lp. p.o. I (example 1)
II (example 2)
N- (3'-dimethylamino-
propyl) -3-chloro-
phenothiazine
(known) 35
50
to 55
28 70
99
to 106
69 170
199
to 218
185

The experiments show that the compounds I and II are effective antiemetics. The above results have also been confirmed in human medicine, and the treatments gave results under those of pharmacodynamics_ appropriate clinical ^ conditions no signs of intolerance.

The N - (2 - diethylaminoethyl) - 2 - methoxy - 3,4 - _χ or -4,5-methylenedioxybenzamide and their pharmacologically non-toxic acid addition salts are usually obtained by reacting 2-methoxy-3,4- or - 4,5-methylenedioxybenzoic acid with N-ethyl-5-phenylisoxolium-3'-sulfonate and subsequent reaction of the product obtained with N, N-diethylethylenediamine and optionally conversion of the amide obtained into a pharmacologically non-toxic acid addition salt.

example 1

N- (2-diethylaminoethyl) 2-methoxy-3,4-methylenedioxybenzamide

It is known that it is of great importance that a drug should not have a cataleptic effect. How out the numerical values in Table 4 can be seen, with 50 mg of compounds I and II only achieved an effect of 20%, whereas as little as 7 mg of the N- (3'-dimethylaminopropyl) -3-chlorophenothiazine already cause a 50% effect.

Furthermore, the benzamides I and II have overall more favorable toxicity values than the N- (3'-dimethylaminopropyl) -3-chlorophenothiazine, as can be seen from Table 5.

37.9 g (0.193 mol) of 2-methoxy-3,4-methylenedioxybenzoic acid and 19.5 g (0.193 mol) of triethylamine are dissolved in 400 ml of anhydrous acetonitrile. This solution is added to a suspension of 49 g (0.193 mol) of N-ethyl-5-phenylisoxolium-3'-sulfonate in 600 ml of anhydrous acetonitrile cooled to 0 ° C, and then left for 45 minutes at ordinary temperature. The reaction mixture is then ^{cooled to 0} ° C. and 45 g (0.386 mol) of N, N-diethylethylenediamine are added while stirring, the solid substance slowly dissolving. Stirring is continued for 4 hours at ordinary temperature, and then the mixture is allowed to stand overnight. The resulting solution is then concentrated to a small volume in vacuo and then 50 ml of water, 50 ml of benzene and 20 ml of 10N sodium hydroxide solution are added. The benzene layer is then separated off, washed with water, dried over sodium sulfate and the benzene is then distilled off in vacuo, 54.1 g of N - (2 - diethylaminoethyl) 2 - methoxy - 3,4 - methylenedioxybenzamide being obtained as an oily residue. The base is then dissolved in absolute alcohol and an excess of a solution of absolute alcohol containing 10% gaseous hydrogen chloride is added to the solution. The warm solution is then diluted with ether until crystallization occurs. occurs. The crystals are filtered off and washed on the filter with ether. There are 46.2 g of N- (2-diethylaminoethyl) - 2 - methoxy - 3,4 - methylenedioxy-

Benzamide hydrochloride (yield: 73%) of mp 164 up to 165 ° C.

Example 2

N- (2-diethylaminoethyl) 2-methoxy-4,5-methylenedioxybenzamide

39.2 g (0.2 mol) of 2-methoxy-4,5-methylenedioxybenzoic acid are dissolved in a mixture of 200 ml of anhydrous acetonitrile and 20.5 g (0.2 mol) of triethylamine. This solution is added with stirring to a suspension of 50.5 g (0.2 mol) of N-ethyl 5-phenylisoxolium-3'-sulfonate in 400 ml of anhydrous acetonitrile. The mixture, cooled with the aid of an ice bath, is stirred first for 1 hour and then for 2 hours at ordinary temperature. Then 46 g (0.4 mol) of N, N-diethylenediamine are added to the ^{solution, which has been cooled to 0 ° C., while stirring}

added, then the whole thing is left to stand overnight at ordinary temperature and then concentrated to a small volume in vacuo. Then the mixture is mixed with 50 ml of benzene, 50 ml of water and 20 ml of 10 η sodium hydroxide solution are added, the benzene layer is separated off, washed with water and dried over sodium sulfate. The benzene is now completely removed in vacuo, with 50 g of one leaving pale yellow oil. This is dissolved in absolute alcohol and with an excess Solution of absolute alcohol, which contains 15% gaseous hydrogen chloride, added. The received warm The solution is then diluted with ether, the N - (2 - diethylaminoethyl) - 2 - methoxy - 4,5 - methylenedioxybenzamide hydrochloride fails. The compound is suctioned off and washed on the filter with ether. 35.5 g (63%) of the hydrochloride are obtained from 213 to 215 ° C.

ORIGINAL INSPECTED

Claims (1)

Claim: N - (2 - diethylamine ethyl) - 2 - methoxy-3,4 - resp. 4,5-methylenedioxybenzamide and its pharmacologically non-toxic acid addition salts. The invention relates to the N - (2 - diethylaminoethyl) - 2 - methoxy - 3,4 - or 4,5 - methylenedioxybenzamide and their pharmacologically non-toxic acid addition salts. These benzamides possess valuable pharmacological properties and can be very effective Antiemetics, neuroleptics, psycholeptics and analgesics be used. In comparative experiments from this table it can be seen that the antiemetic Activity of the compounds of Examples 1 and 2 towards N - (3 '- dimethylaminopropyl) 3 - chlorophenothiazine and partly also against the N - (diethylaminoethyl) - 2 - methoxy - 4 - amino 5-chlorobenzamide is considerably better. It should also be mentioned that the compounds I and II in In contrast to N - (3 '- dimethylaminopropyl) 3-chlorophenothiazine never cause Parkinson's disorders at any high doses.